Chemoanatomic changes associated with aging in vestibulo-sympathetic pathways

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DESCRIPTION (provided by applicant): Changes in body position and posture are detected by the vestibular system and are normally accompanied by rapid modifications in blood pressure. These compensatory adjustments, which allow humans to stand up without fainting, are mediated by functional integration of the vestibular system and blood pressure control mechanisms in the caudal medullary reticular formation: signals from the vestibular otolith organs provide the primary source of input to the shorter latency vestibulo-sympathetic reflex (VSR), while arterial baroreceptors regulate sympathetic tone via the relatively long- latency baroreflex. Although the clinical literature has consistently reported a decline in vestibulo-autonomic function with age, and this decline is associated with increased risk of falling and increased mortality in older people, the cellular mechanisms underlying this loss of function are not known. The overall goal of this two-year exploratory project is to identify chemoanatomic alterations in key caudal brainstem sites of aged rodents, correlated with assessment of VSR and baroreflex function. The two specific aims are (1) to obtain physiological measures of autonomic activity, particularly heart rate and blood pressure (a) under baseline conditions, (b) in response to baroreflex activation and (c) in response to vestibular stimulation in young-adult and aged rats and mice; and (2) to visualize Fos protein, and transmitter and modulator expression in medullary regions activated by the three conditions of Aim 1, in young adult and aged rats and mice. This research will evaluate the overall hypothesis that specific alterations in the chemical anatomy of the caudal medulla parallel an age-dependent decline in VSR and baroreflex control of blood pressure. The project will also assess the utility of two common rodent models of aging for studies of vestibulo-autonomic structure and function. PUBLIC HEALTH RELEVANCE: Rapid adjustments in blood pressure normally accompany movements and changes in body position and posture; these compensatory adjustments allow humans to stand up without fainting. Orthostatic hypotension, which is highly prevalent in the elderly, occurs when the vestibulo-sympathetic reflex fails to mediate such compensatory adjustments. This project will evaluate the hypothesis that specific alterations in the chemical anatomy of the caudal medulla parallel an age-dependent decline in vestibulo-sympathetic- and baroreflex control of blood pressure, thereby suggesting new pharmacotherapies to ameliorate orthostatic hypotension and more specific anti-hypertensive medications that do not elicit disabling vestibular side effects such as dizziness and vertigo.